KR100256867B1 - L-muscone as medicament - Google Patents

Abstract

PURPOSE: The use of L-muscone by which cardiac circulatory, central nervous and cerebral diseases are prevented and treated is provided, which can be used as a substitute of musk during the production of herb medicine preparations. CONSTITUTION: This preparation for cardiac and circulatory system containing L-muscone as a main ingredient has an inhibiting effect on blood relaxation, blood pressure dropping and depression of heart acceleration. The preparation can be orally administered with daily doses of 50 to 10,000 microgram, preferably 50 to 1,000 microgram.

Description

Medical use of l-muscone

1 is an effect on the mean blood pressure and heart rate upon intravenous administration of cats anesthetized L-muscone.

Figure 2 is the effect of blood pressure upon intravenous administration to cats anesthetized L-muscone (l-muscone).

Figure 3 is an effect on the cardiac contractility of l-muscone in the extraction right atrium of rabbits.

Figure 4 is an effect on the heart rate of l-muscone in the extraction right atrium of rabbits.

5 is a glass variation of [ ³ H] 5-HT caused by the hypoxic state.

6 is the effect of l-muscone on the [ ³ H] 5-HT glass fluctuations in the normal and hypoxic state.

Figure 7 is a comparison of the [ ³ H] 5-HT glass growth rate by L-muscone administration in normal and hypoxic state.

Figure 8 is the effect of L-muscone on blood pressure in congenital hypertensive rats.

9 is the effect of l-muscone on heart rate in congenital hypertensive rats.

Figure 10 is the effect of inhibiting palpitations of l-muscone (l-muscone).

Figure 11 is the effect of l-muscone on heart rate in congenital hypertensive rats.

The present invention relates to the medical use of l-muscone having a prophylactic and therapeutic effect on the cardiovascular system, the central nervous system and brain diseases.

Musk is traditionally prescribed as a fragrance regulation in oriental medicine with cow sulfur, cephalocampus, stone spear, benzoin, and mussel oil (sintered fragrance). It is an important expensive herbal medicine that has been widely used in the field, etc. Musk's medicinal and pharmacological effects have been reported to express cardiovascular, central nervous system, antibacterial, anti-inflammatory, androgenic effects, antithrombotic and detoxifying effects. .

The main pharmacological action of musk is expressed by the components of musk's components, and muscone, the musk's main ingredient, has been studied for its efficacy and pharmacology. Only sedation results were reported. For the sedation, the mouse voluntary momentum measurement experiment showed that the muscone showed a significant sedation, especially in exercise excitement. It has been reported that it has a similar effect to apomorphine, which shows excitement (Kimura et al., Journal of Medical and Pharmaceutical Society for Wakan-Yaku 3,324-325, 1986), and Langen, a target of morphologically isolated heart specimens, for the cardiovascular system. Increased blood flow in Langendorf specimens and dose-dependent heart rate in atrial specimens Increase in the (Toyoguchi et al., Applied Pharmacology and Therapeutics, 33 (4) 701-706, 1987) have been reported.

In addition, transient anesthesia and dose-dependent bradycardia were observed in anesthetized rats, and the cardiac effect was apparent due to the decrease in the number of beats and the increase in contraction tension of the extracted core roots. There have been reports of a decrease in the number of patients and an increase in respiratory amplitude. (Matsbara, 1990)

For detoxification and drug metabolism, dose-dependent cytochrome p-450, a hepatic metab olizing enzyme, is induced (Peng et al., 1986), and this form of induction Is similar to the result after treatment with phenobar bital (Tanaka et al., 1987; Tanaka et al., Biochem. Pharmacol. 41 (3), 472-473, 1991).

However, the muscone used in the above-mentioned experiments could not be accurately judged from the pharmacological experiments because the physicochemical was not specifically mentioned as d-, 1- or d, 1-form. .

Therefore, in order to verify the efficacy and effect of these muscones, we have studied the pharmacological action for several years with L-muscone, which is the main ingredient of natural musk, It is concluded that the present invention is effective for cardiac circulation, central nervous system, respiratory system, circulatory action (vascular relaxation, hypotensive action and cardiac contractility), cardiac action (contraction and contraction frequency to heart), central nervous system, brain disease and respiratory system. This study was completed to be used as a raw material for medicines with brain diseases and respiratory stimulation effects.

L-muscone, which has the effect and effect of musk sheep, could not be put to practical use because it is almost impossible to mass-produce by simple synthetic method, but this time, after 10 years of research in our company, dl-muscone has high yield and high purity. And methods of mass production at low cost [Patent Application No .: 22981 (September 9, 12), 4715 (96. 2. 27), 4716 (96. 2. 27)] In this way, the mass production of l-muscone was made possible (Patent Application No. 43, 44, 45 (97. 1 4)), and in today's complicated modern society, Mental anxiety, such as stress caused by various stresses, pollution of the natural environment and changes in the food culture (for example, hypertension, stroke, etc.), cardiac disorders such as cardiac disorders, respiratory distress, and acute pneumonia. New drugs used to improve or treat symptoms such as autonomic anxiety El for use as a raw material - to develop the new use of a non-scones (l-muscone) is a feature of the present invention.

L-muscone of the present invention has the advantage of being used instead of musk in the preparation of several traditional herbal preparations, such as bovine sulfur cheongsimwon, Ki Eunghwan, centripet and musk leucine, the daily dosage is 50㎍ ~ 10,000㎍ to use It is possible, but preferably 50 μg to 1,000 μg. Routes of administration include all possible routes of administration in oral, intravenous and other clinical routes.

Hereinafter, experimental examples and preparation examples of the effect of L-muscone will be described, and the scope of protection of the present invention is not limited thereto.

Experimental Example 1

Effect on the cardiovascular system (1)

1. Experimental Materials and Methods

1) experimental animals

Healthy cats and rabbits were purchased from Cheil Corp. and used in the experiments for one week in the GLP room.

2) blood pressure and heart rate

Cats were intraperitoneally injected with 35 mg / kg of secobarbital sodium and anesthetized and tracheotomy tubes were used to prevent death from secretions. Physiology containing heparin (200 unit / ml) to expose one femoral artery, insert an arterial cannula, connect it to a pressure transducer, and prevent blood from clotting between the pressure transducer and the cannula After filling the junction with saline, the mean blood pressure and heart rate from the femoral artery were measured. The cannula with 3-way stopcock attached to the same femoral vein was used to inject the drug, and all the drugs were injected slowly and the continuous blood pressure and heart rate were measured. All the drugs were injected with a little saline for injection so that they could not remain in the cannula after the injection, and care was taken not to raise blood pressure due to sudden external injection.

3) Effect of l-muscone on blood pressure and heart rate

L-muscone was suspended in 10% tween 80 and used for the experiment. L-muscone suspensions were slowly injected into the cannula of the femoral vein at concentrations of 50 and 100 mg / kg and the changes in blood pressure and heart rate were observed.

4) Effect of l-muscone on the extracted right atrium of rabbits

The rabbit's heart is extracted and blood is removed from a solution of Klebs-Henseleite saturated with 95% O ₂ /5% CO ₂ . The other one was fixed to the isometric transducer. Basal resting tension was adjusted to 500 mg tension and waited for about 1 hour until the tissue stabilized and used in the experiment. At this time, the temperature of the nutrient solution was maintained at 37 ℃ similar to the temperature in vivo. L-muscone was dissolved in 75% DMSO and used in all experiments. The final concentration of DMSO in the organ bath was adjusted to 0.2% or less. After l-muscone is administered at a concentration of 100 µg / ml, the drug is absorbed for 15 minutes, and isoproterenol is cumulative at a concentration of 10 ^-9 to 10 ^-7 M for 3 minutes. Administration at intervals of less than one hour measured the contractile force and contraction frequency of the right atrium. The control group was administered through the same experimental procedure after administration of the same concentration of DMSO. The experimental results for the cardiac contractile force were expressed in relative proportions with the maximum contraction force being 100%, and the experimental results for the contraction frequency were expressed in the number of contractions per minute.

2. Experimental Results

1) Effect and dose response of l-muscone on cardiovascular system Average blood pressure was 29mmHg and 48mmHg when intravenously injected 50mg / kg and 100mg / kg of l-muscone, respectively. It showed a degree declining effect. On the other hand, in the heart rate it was confirmed that the heart rate decreases about 14 times, 35 times per minute in 50mg / kg and 100mg / kg as a slight dose-dependent reduction effect (Fig. 1, Fig. 2).

2) When the extracted right atrium of the rabbit isopropyl furo terephthalate play (isoproterenol) hayeoteul Continue cumulative administered at 10 ^-9 M were able to confirm the positive inotropic effect and positive chronot ropic effect, the maximum contraction force when hayeoteul administration of 10 ^-7 M Arrhythmia occurred at higher concentrations, so the experiment was conducted with the highest isoproterenol dosage of 10 ^-7 M. Treatment with DMSO (less than 0.2%) and l-muscone (100 µg / ml) in the normal harvested atrial appendage had no effect on contractile force and contraction frequency. However, the pretreatment with l-muscone significantly reduced the positive inotropic and positive chronotropic effects induced by isoproterenol (FIG. 3, FIG. 4).

3. Consideration

In the above results, L-muscone, the main ingredient of musk, decreases blood pressure and heart rate in the cardiovascular system and does not affect the heart in normal condition, but isoproterenol increases cardiac contractility and contraction. The effect of reducing the maximum frequency was found to be effective in calming the excited state such as palpitations.

Experimental Example 2

Impact on cerebral ischemia

1. Experimental Materials and Methods

1) Experimental Animal

Sprague-Dawley male rats (200-250 g) were acclimated for one week in the GLP room and used for the experiment.

2) reagents

5-Hydroxy [G- ³ H] tryptamine creatinine sulfate ([ ³ H] 5-HT) is from Amer rsham, nialamide is from Sigma, and zimedine lidine) was purchased from Research Biochemical and used for the experiment.

3) Production of hippocampal sections

After the rats were sacrificed by the guillotine, the brains were quickly removed, the thigh hemispheres were cut on the ice plate, the cerebral cortex was removed, and the whole hippocampus was obtained. Hippocampal tissues were cut to a thickness of 400 μm in the transverse direction using a McIlwain mechanical tissue chopper (The Mickle Laboratory Engineering Co., Gomshall, Surrey, UK) to obtain hippocampal sections and saturated with 95% O ₂ and 5% CO ₂ . Tissue debris was removed by suspending in cold nutrient solution [NaCl 124 mM, KCl 4 mM, CaCl _{2 2} mM, KH ₂ PO ₄ 1.25 mM, MgSO ₄ 1.0 mM, MaHCO ₃ 25 mM, glucose 10 mM, Nialamide 12.5 μM].

4) Adsorption of [ ³ H] 5-HT and Induced Hypoxia

Hippocampal sections were stabilized for 30 minutes in a nutrient solution at 37 ° C. and adsorbed to the tissue for 20 minutes in a nutrient solution containing 0.1 μM of [ ³ H] 5-HT. The hippocampal tissues were washed three times with the same nutrient solution to remove unadsorbed [ ³ H] 5-HT, and then, 3 ml of fresh nutrient solution was added and incubated for 130 minutes at 10 minute intervals. At this time, 10 μM of zimelidine was added to the nutrient solution used to prevent re-adsorption of free [ ³ H] 5-HT. Hypoxia was induced by exchanging nutrient solution saturated with 95% N ₂ and 5% CO ₂ in the 60 min and 70 min fractions, and test specimens were also treated at the same time.

5) Determination of liberated [ ³ H] 5-HT

Tissue dissolving agent (Soluen 350, Packard Instrument Company, Inc., Downers Grove, IL, USA) was added to the cultured hippocampal tissues, dissolved for 1 hour at 47 ° C, and neutralized by adding 50 µl of glacial acetic acid. Take 1 ml of the culture solution and 0.1 ml of tissue solution, mix well with 9 ml of radioactivity measurement solution (READY SAFE, Beckman Instrument Inc., Fulletron, CA, USA), and then use Liguid Scintillation Counter (Beckman Instrument Inc., Fulletron, CA, USA). ) The radioactivity was measured. The amount of free [ ³ H] 5-HT was expressed as a percentage of the amount adsorbed on hippocampal tissue.

6) Statistical Processing

Each result was expressed as mean ± standard error. Statistical significance was verified by analysis of variance (ANOVA) and the difference between groups was compared using Student New-man Keul test.

2. Experimental Results

1) [ ³ H] 5-HT glass fluctuation caused by hypoxia

The spontaneous release of [ ³ H] 5-HT in the hippocampal section continued, with a rapid decrease in glass initially and a constant glass pattern after 40 minutes (Figure 5). Therefore, in this experiment, the free amount of [ ³ H] 5-HT was expressed as a relative value based on the free amount at 50 minutes, induced hypoxia at 50 and 60 minutes after incubation, and the test specimens were treated, respectively. Spontaneous release of [ ³ H] 5-HT was markedly reduced when hypoxia was induced, and returned to normal when oxygen was resupplied.

2) Effect of l-muscone on [ ³ H] 5-HT Glass Fluctuation

When the concentration of 10 ^-5 M of L-muscone, the main component of musk, in normal oxygen condition, the release of [ ³ H] 5-HT increased significantly compared to the control group. Significantly increased to recover similar to the normal oxygen control (Fig. 6). Comparing the increase rate of [3H] 5-HT release by the administration of l-muscone in the normal and hypoxic states showed more free increase in the hypoxic state (FIG. 7).

3. Consideration

In the above experimental results, it was confirmed that the effect of restoring 5-HT free reduction caused by hypoxia to the normal state when L-muscone, the main component of musk, was administered. In addition, when comparing the increase rate of 5-HT glass in the normal oxygen state and low oxygen state, it was confirmed that L-muscone increased more in the low oxygen state. Therefore, L-muscone, the main component of musk, has an effect of normally restoring the free reduction of 5-HT induced by cerebral ischemia, and L-muscon (l-muscone) having the 5-HT free increasing action (l-muscone). -muscone may reduce the nerve damage caused by cerebral ischemia.

Experimental Example 3

[Effect on Stroke]

In histopathologic examination, cell damage due to cerebral ischemia and reperfusion was inhibited in the L-muscone group, and ATP content inhibited ATP reduction due to cerebral ischemia and reperfusion in the L-muscone group. , Lactate content showed a significant lactic acid inhibitory effect compared to the control group, Lipid peroxidation showed a significant decrease compared to the control group was confirmed to be effective in stroke (see Table 1 and Table 2).

TABLE 1

TABLE 2

Experimental Example 4

Impact on the cardiovascular system (2)

1) Effect on hypertension

As a result of response test for blood pressure of SHR, L-muscone showed significant decrease in blood pressure and heart rate in comparison with the control group (Fig. 8 and Fig. 8). 9)

2) Effect on palpitations

As a result of response test against palpitation in normal rats, L-muscone showed a good palpulation inhibitory effect, and showed a significant inhibitory effect on the heart rate change rate compared to the control group (FIG. 10 and FIG. 11)

Experimental Example 5

Experiment on the action on the respiratory system

1. effects on dyspnea;

For urethane suppressed breathing, the l-muscone group showed an increase in respiratory rate and respiratory depth, and the respiratory excitability was recognized (see Table 3).

TABLE 3

Experimental Example 6

Experiments on the central nervous system

1. effect on sedation;

Rotarod test showed significant sedation in the L-muscone group 0.45 and 4.5 mg / kg compared to the normal group (see Table 4).

TABLE 4

2. effect on spontaneous motor performance;

In the L-muscone group, the 0.15 and 1.5 mg / kg administration groups showed a significant decrease in spontaneous motor performance compared to the normal group (see Table 5).

TABLE 5

3. action on antistress;

① Significantly enlarged adrenal weight after stress was significantly inhibited in the L-muscone 1.5 and 4.5 mg / kg groups compared to the control group.

② Significant decrease in the amount of ascorbic acid in the adrenal gland due to stress was significantly inhibited in the l-muscone 1.5 mg / kg group (see Table 6).

TABLE 6

Experimental Example 7

L-muscone Acute Toxicity Test

1. Sample: l-muscone

2. Experimental Animal

Rats: SPF rats of the 5 week old SD strain

Male: 127.2-144.7g

Female: 112.5 ~ 138.2g

The experimental animals were freely fed solid feed and water under conditions of room temperature 23 ± 3 ° C., humidity 50 ± 10%, illumination time 12 hours (7 am to 7 pm and illuminance 150 to 300 Lux).

3. Method of administration and observation

Five rats of one group were used, and the animals were fasted overnight before administration, and the test substance was orally administered by using a syringe equipped with Sonde for oral administration. Changes in general symptoms were observed at least once daily from the next day to 14 days from 1 hour to 6 hours after administration. LD ₅₀ was not observed because no dead animals were observed.

4. Test Results: The test results are shown in Table 7 below.

TABLE 7

From the above experimental results, it can be seen that the acute toxicity of the l-muscone of the present invention can be ignored.

Preparation Example 1-4

1) Xinwu Hwang Cheongsimwon in 1 round, medicinal powder 282mg, licorice 202mg, ginseng 97mg, turmeric 100mg, singok 100mg, soybean yellow rice 70mg, cinnamon 70mg, glue 70mg, peony 60mg, Mcmundong 60mg, golden 60mg, Angelica 60mg, windproof 60mg, Baek 60mg, Shiho 50mg, Gilyeong 50mg, almond 50mg, Bokryeong 50mg, Cheongung 50mg, Sulfur 14mg, Nutrition angle 35mg, Long head 41mg, Pneumonia 30mg, Health 30mg, 75g of l-muscone is prepared according to the preparation method of the pill.

2) Sinwonbang Hwang Cheongsimwon in one round of medicinal powder 263mg, licorice 188mg, ginseng 94mg, turmeric 94mg, singok 94mg, soybean rhubarb 66mg, cinnamon 66mg, glue 66mg, peony 56mg, mackmundong 56mg, golden 56mg, donkey 56mg, windproof 56mg, Baek 56mg, Shiho 47mg, Gilyeong 47mg, Pedestrian 47mg, Bokryeong 47mg, Cheongung 47mg, Sulfur 45mg, Nutrition angle 38mg, Long-brain 38mg, Whiteworm 28mg, Health 28mg, L-muscone 570 ㎍ according to the preparation method of the pill. .

3) Pyrophoric Acid 282mg, Licorice 202mg, Ginseng 97mg, Sulfur 100mg, Singok 100mg, Glycine 70mg, Cinnamon 70mg, Glue 70mg, Peony 60mg, Macmundong 60mg, Golden 60mg, Angelica 60mg, Windproof 60mg, Baek 60mg , Shiho 50mg, Gilyeong 50mg, almond 50mg, Bokryeong 50mg, Cheongung 50mg, Sulfur 14mg, Nutrition angle 35mg, Long head 41mg, Pneumonia 30mg, Health 30mg, 75μg according to the preparation method of the liquid formulation do.

4) Acid Medicinal Powder 263mg, Licorice 188mg, Ginseng 94mg, Sulfur 94mg, Singok 94mg, Soybean Yellow Soybean 66mg, Cinnamon 66mg, Glue 66mg, Peony 56mg, Macmundong 56mg, Golden 56mg, Angelica 56mg, Windproof 56mg 56mg, Shiho 47mg, Gilyeong 47mg, Pedestrian 47mg, Refuge 47mg, Cheongung 47mg, Sulfur 45mg, Nutrition angle 38mg, Brain 38mg, White worm 28mg, Health 28mg, L-muscone 570㎍ according to the preparation method of the liquid Manufacture.

Claims (2)

A cardiovascular system having an effect of releasing blood vessels, lowering blood pressure, and palpitations, containing L-muscone as a main component. The cardiovascular system according to claim 1, wherein the daily dose is 50 to 1000 µg.

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